Dual-frequency ultrasound activation of nanomicellar doxorubicin in targeted tumor chemotherapy.

Introduction: This study investigated the therapeutic effect of dual-frequency sonication (3 MHz and 28 kHz) at low intensity levels in combination with micellar doxorubicin in the treatment of a tumor model of spontaneous breast adenocarcinoma in Balb/c mice. Methods: We used sonication frequencies 28 kHz and 3 MHz and their dual combinations in the progressive wave mode to enhance acoustic cavitation. Then, the antitumor effect of the simultaneous dual-frequency ultrasound (28 kHz and 3 MHz) at low intensity levels in combination with doxorubicin and micellar doxorubicin injection was investigated in a spontaneous model of breast adenocarcinoma in Balb/c mice. Sixty-three tumor-bearing mice were randomly divided into seven groups: control, sham, sonication with dual frequency, doxorubicin without sonication, doxorubicin with dual-frequency sonication, micellar doxorubicin without sonication, and micellar doxorubicin with dual-frequency sonication. The tumor volume change relative to the initial volume, tumor growth inhibition ratio, the required times for each tumor to reach two ( T) and five ( T) times its initial volume, and survival period were the tumor growth delay parameters which were calculated and recorded at various times after treatment. Results: The results of the combination of frequencies 28 kHz (0.04 W/cm) and 3 MHz (2.00 W/cm) showed remarkable enhancement of the cavitation activity compared with single-frequency sonication ( P < 0.05). The micellar doxorubicin injection with sonication group showed a significant difference in the relative volume percent parameter compared with the other groups ( P < 0.05). Additionally, the T and T times in the micellar doxorubicin with sonication group were significantly higher than in the other groups ( P < 0.05). Also, the survival period of the mice in the micellar doxorubicin with sonication group was significantly longer than in the other groups ( P < 0.05). These findings were verified histopathologically. Conclusion: This study shows that simultaneous combined dual-frequency ultrasound sonication in continuous mode is effective in producing cavitation activity at low intensity. We conclude that dual-frequency sonication with micellar doxorubicin injection extends survival in a murine breast adenocarcinoma model. [ABSTRACT FROM AUTHOR]